Jane B. Acri

Assessment of cocaine-like discriminative stimulus effects of dopamine D3 receptor ligands

The highly selective dopamine D3 receptor ligand, (+)-PD 128907 4aR10bR-(+)-trans-3,4,4a,10b-tetrahydro-4-n-propyl-2H5H[4,3- b]-1,4- oxazin-9-ol), and other dopamine D3 receptor ligands, (+/-)-7-hydroxy-2-(N,N-di-n-propylamino)tetralin and (+)-7-hydroxy-2-(N,N-di-n-propylamino)tetralin, substituted for the discriminative stimulus effects of cocaine in rats, an animal model of subjective effects in humans. Substitution only occurred at doses that markedly decreased responding. These results suggest that dopamine D3 receptors may be involved in the subjective effects of cocaine, and therefore may be a target for the discovery of treatments for cocaine dependence.

Modulation of pre- and postsynaptic dopamine D2 receptor function by the selective kappa-opioid receptor agonist U69593 †

The repeated administration of selective kappa‐opioid receptor agonists prevents the locomotor activation produced by acute cocaine administration and the development of cocaine‐induced behavioral sensitization. Previous studies have shown that dopamine (DA) D2 autoreceptors modulate the synthesis and release of DA in the striatum. Evidence that kappa agonist treatment downregulates DA D2 receptors in this same brain region has recently been obtained. Accordingly, the present studies were undertaken to examine the influence of repeated kappa‐opioid receptor agonist administration on pre‐ and postsynaptic DA D2 receptor function in the dorsal striatum using pre‐ and postsynaptic receptor‐selective doses of quinpirole. Rats were injected once daily with the selective kappa‐opioid receptor agonist U69593 (0.16–0.32 mg/kg s.c.) or vehicle for 3 days. Microdialysis studies assessing basal and quinpirole‐evoked (0.05 mg/kg s.c.) DA levels were conducted 2 days later. Basal and quinpirole‐stimulated locomotor activity were assessed in a parallel group of animals. The no‐net flux method of quantitative microdialysis revealed no effect of U69593 on basal DA dynamics, in that extracellular DA concentration and extraction fraction did not differ in control and U69593‐treated animals. Acute administration of quinpirole significantly decreased striatal DA levels in control animals, but in animals treated with U69593, the inhibitory effects of quinpirole were significantly reduced. Quinpirole produced a dose‐related increase in locomotor activity in control animals, and this effect was significantly attenuated in U69593‐treated animals. These data reveal that prior repeated administration of a selective kappa‐opioid receptor agonist attenuates quinpirole‐induced alterations in DA neurotransmission and locomotor activity. These results suggest that both pre‐ and postsynaptic striatal DA D2 receptors may be downregulated following repeated kappa‐opioid receptor agonist administration. Synapse 39:343–350, 2001. Published 2001 Wiley‐Liss, Inc.

Repeated treatment with the selective kappa opioid agonist U-69593 produces a marked depletion of dopamine D2 receptors

U‐69593, the selective κ‐opioid agonist, was repeatedly administered in single daily injections (0.32 mg/kg) to male, Sprague‐Dawley rats. Two or ten days later, the rats were euthanized and dopamine D1 and D2 receptors were measured using (3H]SCH 23390 or [3H]sulpiride, respectively, in caudate putamen and nucleus accumbens. Two days after the last of three injections, dopamine D2 receptors in the caudate putamen were decreased by approximately 40%, with no change in D1 receptors. Dopamine D2 receptor number had returned to normal by 10 days posttreatment. In contrast, in the nucleus accumbens there was a small, nonsignificant decrease in dopamine D2 receptors 2 days after treatment, but a large increase (65%) after 10 days. In agreement with the changes in D2 receptors, there was a significant downward shift in the locomotor activity curve for the D2 agonist quinpirole after a 2‐day withdrawal. There were no differences in either the total amount of dopamine taken up or in the IC50 for cocaine to inhibit dopamine uptake following this treatment, suggesting that the dopamine transporter and presynaptic terminals were intact. The results of these studies demonstrate that repeated administration of a selective κ‐opioid agonist induces long‐term alterations in dopamine D2 receptors. Furthermore, the finding that these changes in receptor number require both repeated injections and a withdrawal time greater than 1 day suggests that these alterations are compensatory in nature. Synapse 30:275–283, 1998.

Biotechnology and the Treatment of Addictive Disorders

Addiction is a chronic relapsing illness with onset typically occurring in the early teenage years, followed by cycles of drug use and abstinence. The disease is mitigated by complex interactions between genes and environment. Viewed as such, the treatment of addiction could span the whole lifetime of the patient and, ideally, should be tailored to the illness cycle. The search for effective treatments has intensified recently due to our better understanding of the underlying neurobiologic mechanisms contributing to drug use and relapse. The three main types of treatment are behavioral, pharmacologic and, more recently, immunologic therapies. Vaccines and monoclonal antibodies are being developed mainly for stimulant use disorders and nicotine addiction. In addition, new molecular targets identified by preclinical research have shown promise and are awaiting proof-of-concept studies in humans. The main focus of this review is on the development of immunotherapy for stimulants and nicotine addiction as a model highlighting the current status of the science and potential emerging discoveries and development.

Stereospecific transduction of behavioral effects via diazepam-insensitive GABAA receptors

Previous studies reported a positive correlation between ligand affinities at diazepam-insensitive GABAA receptors and substitution for the discriminative stimulus effects of the benzodiazepine receptor antagonist, flumazenil, in pigeons. In the present experiments, bretazenil and Ro 14-5974 (ethyl-(S)-11,12,13,13 a-tetrahydro-9-oxo-9H-imidazo[1,5-a]-pyrrolo-[2,1-c] [1,4]benzodiazepine-1-carboxylate) partially substituted for, and blocked the discriminative stimulus effects of midazolam, congruent with their actions at diazepam-sensitive GABAA receptors in vitro. In addition, bretazenil and Ro 14-5974, but not their R-enantiomers, had high affinity for diazepam-insensitive receptors and fully substituted for the discriminative stimulus effects of flumazenil. The R-enantiomers of these compounds had low affinity (Ki > 1 microM) for diazepam-sensitive and diazepam-insensitive receptors, and did not share discriminative stimulus effects with flumazenil or midazolam. Ro 19-0528 (7-chloro-3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-4,5-dihydro-5-met hyl-6H- imidazo[1,5-a][1,4]benzodiazepin-6-one), a structurally related compound with full agonist actions at diazepam-sensitive GABAA receptors, had high diazepam-insensitive receptor affinity (Ki = 96 nM) and partially substituted for the discriminative stimulus effects of flumazenil. These results are consistent with stereospecific mediation of the discriminative stimulus effects of flumazenil through high affinity binding to diazepam-insensitive receptors in pigeons.

Dopamine D3 Receptor Antagonist (GSK598809) Potentiates the Hypertensive Effects of Cocaine in Conscious, Freely-Moving Dogs

The chronic and relapsing nature of addiction presents unique challenges for ensuring the safety of a potential medication. A patient may use cocaine, for example, while taking the medication or take more medication than prescribed. Thus, a potential medication must be safe and not exacerbate the effects of cocaine. Multiple published studies support antagonism of brain dopamine D3 receptor function as a potential mechanism of action for an anti-addiction medication. Dopamine D3 receptors are widely distributed outside the central nervous system, however; for example, dopamine D3 receptors in the kidneys are implicated in regulating blood pressure. The selective dopamine D3 receptor antagonist GSK598809 [1-(2-fluoro-4-trifluoromethyl-phenyl)-3-{3-[4-methyl-5-(4-methyl-oxazol-5-yl)-4H-[1,2,4]triazol-3-ylsulfanyl]-propyl}-3-aza-bicyclo[3.1.0]hexane] has been proposed as a medication to treat cocaine and other substance use disorders. The US Food and Drug Administration has established guidelines recommending safety studies to investigate potential undesirable pharmacodynamic effects of a substance in relation to exposure in the therapeutic range and above. Hence, we assessed the interaction between this selective dopamine D3 receptor antagonist and cocaine on hemodynamics and cardiac function in freely-moving, telemetered dogs before conducting a clinical trial. GSK598809 increased the hemodynamic effect of cocaine in this model. Thus, the increase in blood pressure after intravenous cocaine was greater in animals that had been pretreated with GSK598809 compared with vehicle. This finding suggests that GSK598809 in particular, and perhaps dopamine D3 receptor antagonists as a class, may produce unacceptable cardiovascular risks as medications to treat cocaine use disorder.

From bench to bedside: mGluR2 positive allosteric modulators as medications to treat substance use disorders

ObjectiveThis paper provides an overview of the role of type 2 metabotropic glutamate receptors (mGluR2) in addiction and behaviors reflecting addictive processes.ResultsAZD8529, an mGluR2 positive allosteric modulator (PAM), failed to separate from placebo in a phase II schizophrenia trial. The demonstration by Athina Markou’s laboratory that AZD8529 attenuated both nicotine self-administration and cue-induced reinstatement was a key factor in the decision to move this compound into a smoking cessation study.ConclusionHere, we highlight Markou laboratory’s contribution to this project, as well as several innovative features of the phase II clinical trial that has already completed enrollment with top line results expected in early 2017.

Drug Discovery and Development for Reward Disorders: Views from Government

Publisher Summary This chapter discusses governments outlook in the drug discovery and development for reward disorders. The National Institute on Drug Abuse (NIDA) is the worlds largest research institution dedicated to funding research on drugs of abuse, prevention of drug abuse, and treatment of substance abuse disorders. The Division of Pharmacotherapies and Medical Consequences of Drug Abuse (DPMC) initiated a discovery and development program in 1990. The initial program intended to perform standardized tests and clinical studies to facilitate the discovery and development of addiction medications and to facilitate the involvement of the pharmaceutical industry and academia. The primary objective of this discovery program was to discover putative medications for the treatment of cocaine dependence. The structure, objectives, and testing scheme of the NIDA drug discovery programs have changed as a result of the maturing of the science and efforts to improve efficiency. Medication targets have expanded and relapse prevention has become the number one focus. The motivation for Federal involvement in the development of medications for the treatment of addictive disorders is from a public health viewpoint. They are heavily invested in the treatment of addictive disorders and views new medications to treat these disorders as a way to expand treatment and improve the public health of the United States.